THE RELATIONSHIP BETWEEN CHOLINESTERASE INHIBITION AND DRUG-INDUCED FACILITATION OF MAMMALIAN NEUROMUSCULAR TRANSMISSION

¹ Departments of Pharmacology, New York University School of Medicine and Cornell University Medical College, New York, N. Y.

Twitch potentiating potencies and anticholinesterase activities were ascertained for a series of quaternary ammonium ions. The slopes of the calculated dose-potentiation lines divide these ions into a steeper and lesser sloped class called Group I and Group II, respectively. Group I includes meta-carbamyl, meta-hydroxyl and para-hydroxyl phenyltrialkylammonium ions. Group II comprises non-substituted phenyltrialkylammonium ions, ortho-substituted phenyltrimethylammonium ions and aliphatic ions. The maximal potentiating responses obtainable with Group II ions are far below those given by Group I ions.

In Group I a perfect correlation between twitch potentiating potency and anticholinesterase activity was established. This was not the case with the Group II ions. Furthermore, several Group II compounds had greater anticholinesterase activity than some Group I compounds although the latter were more effective twitch potentiators. Finally, compounds which produced only neuromuscular depression were indistinguishable from many of the facilitatory agents in terms of anticholinesterase activity.

The structure-activity data indicated that the common structural basis for twitch potentiation resides with the onium grouping. The onium center which provides optimal activity is diethylmethylammonium. An appropriate ring substituent further enhances potency, the optimal substituent being a carbamyl group meta oriented to the onium center.